\chapter{Laboratory Information Management Systems}
\label{limsBackground}

\index{LIMS}

A laboratory information management system (LIMS) is a software system that is capable of managing laboratory samples, users, instruments, and data. LIMS come in many varieties, reaching from the more expensive enterprise solutions, often designed to link laboratory systems to an organization's business systems; to the classic approach where users just want a LIMS to track their data and samples, and to generally optimize their laboratory's day-to-day operation. The content of this chapter is based on \cite{limsHowTo} and \cite{limsArticle}.

\section{History}

Laboratory management software was first conceived by the pharmaceutical industry in the late 1960s. The late 1970s and early 1980s gave us the first commercially available LIMS. There is disagreement to when the first LIMS was offered, but Beckman Coulter's Laboratory Automation Operation introduced a commercial laboratory management software package in 1979, while the term LIMS was first introduced in 1981 by the release of Perkin Elmer's LIMS/2000 according to \citeauthor{limsArticle} \cite{limsArticle}.

\section{Requirements}
\label{sec:limsRequirements}

Every laboratory has different requirements, priorities, and needs when it comes to their information systems, but with the vast amount of LIMS available today, both commercially available and open source systems, there is a possibility that there already exists a LIMS that fits a laboratory's requirements. Ultimately, the needs and circumstances of the environment where the LIMS is to be used determine what factors are relevant when evaluating the software. Open source and commercial LIMS each have their own advantages and disadvantages that should be taken into consideration. As a starting point it can be useful to look at cost, flexibility and security when comparing the different alternatives. Thus it is crucial to define the budgetary limits and the system requirements before comparing and deciding on a LIMS solution.

\subsection{Cost}
\label{commercialOrOpenSource}

When putting the cost of open source and commercial LIMS in the balance one must look at the total cost of ownership. In terms of start-up price, commercial systems tend to be more expensive than their open source counterpart(s). Open source solutions are usually available free of charge, although some commercial solutions are also provided as open source software. The cost of software should not be assessed merely on the initial cost of acquiring the system, the cost of maintenance and support throughout the software's lifecycle should also be considered. 

Choosing open source LIMS solutions has become a trend among MS proteomics groups, but choosing such software solutions may require more bioinformatics resources than originally planned. More resources spent means higher cost.

\subsection{Flexibility and usability}

A common argument for utilizing open source solutions is that they are more flexible compared to commercial software. With open source solutions one can examine the source code, and if necessary make alterations in order to get the system to behave as desired, or to fix any problems with the source code. The same advantage is not present for commercial solutions with closed source code, but neither of the two solutions have a clear advantage when it comes to fixing bugs and security issues. Software providers provide fixes for their commercial software, fixes that are expected to remove the problem without introducing new issues. The quality of updates to commercial software is ensured through rigorous testing before being released. This might not be the case for community developed fixes to open source software, which may be refined over several iterations if the bug is not completely resolved on the first try.

A high degree of flexibility will provide the LIMS with the ability to easily meet the future needs of the laboratory. A flexible LIMS should have the ability to interface with new instruments as they become available, and should thus be easily expandable and able to support new technologies. The system's flexibility can be partly measured by how these changes are made. Typically, the less programming required after implementation of the LIMS, the more user-friendly it is. The single most important feature for any information system is usability.

Utilization of open source LIMS requires that the software creators are keeping the program current and compatible with new developments of third party analyses and provide bug fixes for known security problems. The source code of open source software is available for the user to freely change and improve the software when necessary. When customizing open source software one should make sure that the changes made are compatible with future updates provided by the original developers. Making changes to the source code often leads to \index{Forking}forking, a phenomenon occuring when developers modifies the source code in such a manner that subsequent changes or improvements to the source code of one version of the software is not applicable to other versions. Forking may lead to compatibility issues with previous versions, which in turn may lead to higher costs of maintaining the system.

An important point to consider is whether or not a system is ready to use ``out of the box'', if it is custom built for a particular laboratory's needs, or if it is a hybrid of the two. Custom built systems will usually take significantly longer to implement, and might require more resources and maintenance than a system with no need for customization.

Where the program will be installed and where it will run is also important to consider. There are a few alternative solutions, each with their own advantages and disadvantages. Software may be installed and run on the individual users' computers, performing all the processing locally, with a central database storing the data. A slightly different approach is to  install the software and perform both the processing and data storage on a central server, typically by providing the users with a web-based interface enabling the system to be accessed from any location with an active Internet connection. Hybrids of these two alternatives are also feasible solutions, although less commonly implemented. A solution where both the data processing and storage happens on a central server is practical from a maintenance perspective due to the fact that no programs (other than e.g. a web browser) need be installed and maintaned on the user's computer.

\subsection{Security}

A LIMS should provide a varying level of privilege and access rights to reduce the risk of accidental modification and loss of data. Restricting the privileges and access rights of users does not only provide a more secure environment for modifying and storing data, it also enables the LIMS to provide limited access to collaborators. Limited access to the LIMS is provided to external collaborators or customers by some laboratories, granting the collaborators access only to their own data.  A LIMS providing sample tracking and an audit trail is also more secure than a LIMS that does not provide these features, as changes are easily traced and data easily recovered if necessary.

Comparing security levels of commercial and open source solutions may not be done based solely on the method of development and distribution. Open source has been argued to be more secure than commercial products due to the fact that the source code is publically available for review. The same argument has however been used to demonstrate the opposite, as it may be easier to uncover flaws when the source code is available. The bottom line is that some commercial products are less secure than their open source alternatives, and vice versa. How the software is updated and maintained by the user when security flaws are discovered is just as important as the software having implemented reliable security mechanisms.

\section{Existing LIMS systems}
\label{existingLIMSSystems}

We uncovered PROBE's requirements for an information system in Chapter~\ref{chap:goals}. As mentioned in Section~\ref{sec:limsRequirements} there are many different LIMS available. Before the implementation of HP LIMS was started, existing LIMS solutions were considered, both commercial and open source. We quickly narrowed our scope to a few alternatives, the most prominent being Nautilus LIMS, Proteios and OpenFreezer. All these systems cover important aspects of the processes occuring in typical laboratories.  Ultimately, OpenFreezer was discovered to be an unsuitable alternative as it did not provide many of the features wanted for our LIMS, so we ended up with two different alternatives for further evaluation: Nautilus LIMS and Proteios. Table~\ref{tab:limsOverviewTable} provides a comparison of Nautilus LIMS and Proteios, and lists some of the criteria that are important for our evaluation of the software packages.

\definecolor{myblue}{RGB}{153,204,255}
\newcolumntype{g}{>{\columncolor{myblue}}p{4cm}}
\begin{table}
\caption{LIMS evaluated for use, commercial and open source \label{tab:limsOverviewTable}}
\centering
    \begin{tabular}{ g p{2.7cm} g }
        \hline
        \bf Product                                & \bf Nautilus LIMS     & \bf Proteios   		\\ \hline
        \bf Year debuted                           & 1998                  & 2007       		\\ \hline
        \bf Cost                                   & Not available         & Free, open source		\\ \hline
        \bf Customized or out of the box?          & Both                  & Customized 		\\ \hline
        \bf How to make changes to workflow        & Menus and programming & Menus and programming  	\\ \hline
        \bf How to add entities to database        & Menus and programming & Programming  		\\ \hline
        \bf Multilingual                           & Yes                   & Yes        		\\ \hline
        \bf Third-party databases                  & None                  & IPI, Swiss-Prot, TrEMBL, UniProt	\\ \hline
        \bf Third-party search engines or software & None                  & Mascot, X! Tandem		\\ \hline
        \bf Has sample tracking or audit trail?    & Yes                   & Sample tracking only	\\ \hline
        \bf Has varying levels of access (security)?& Yes                  & Yes         	        \\ \hline
    \end{tabular}
Table data gathered from \cite{limsArticle}
\end{table}

\subsection{Nautilus LIMS}

Thermo Fisher Scientific provides Nautilus LIMS, a system that has been on the market since 1998 and has been under constant development since. Nautilus LIMS provides many important features that simplifies the workflow in a laboratory, such as extensive sample tracking and an audit trail. Varying access (authorization) levels, and the possibility to make changes to the workflow and add database entities, both through menus within the application and through programming, is provided. Although it does include many of the features wanted, the system lacks a few key features that were deemed very important in our evaluation process. Also, modifications requiring programming have to be performed by the software vendors as Nautilus LIMS is not provided as open source software.

Nautilus LIMS does not utilize any third-party databases or search-engines, or other software necessary to provide the desired functionality described in Chapter~\ref{chap:goals}, as can be observed in Table~\ref{tab:limsOverviewTable}. With no open source code to modify, we would be dependent on the software vendors to implement the desired features that are currently not present in the software. Nautilus LIMS is more aimed towards secure storage of data and sample tracking in the laboratory, and customizing Nautilus LIMS to become a storage solution with the possibility of functioning as an important tool in the order- and validation process of heavy peptides, a key goal of any new information system PROBE acquires for organizing their heavy peptides, was considered too expensive. In addition, the initial cost of Nautilus LIMS combined with potentially high maintenance costs deemed this solution inappropriate.

\subsection{Proteios}

Proteios is a relatively new LIMS compared to Nautilus LIMS and others, having been on the market since 2007. Proteios aims to provide the users with tools enabling the management and connection of data from several different sources relevant to an experiment - sample processing, MS, and protein identification \cite{proteios}. Several third party databases and search engines are utilized in Proteios to accomodate these features, see Table~\ref{tab:limsOverviewTable}. However, it does not provide a BLAST tool.

Changes to workflow can be made both through the system's menus and through programming, and like Nautilus LIMS, Proteios provides sample tracking, but it does not provide an audit trail. Proteios is an open source project which can be extended by anyone, and the software is fully customizable. For these reasons Proteios was considered a reasonable candidate on which to base a LIMS solution. By customizing open source software one can quickly make changes that are not compatible with later versions of the software provided by the original developers, possibly turning, e.g., security updates to the original software into nuisances instead of advantages, and this concern discouraged a decision favoring Proteios as an appropriate candidate.

\section{Conclusion}

Although the systems we have evaluated do provide the essential LIMS features needed, such as persistent storage of data in a central database and varying levels of access (security), they do not provide all of the features described in Chapter~\ref{chap:goals}. Nautilus LIMS is a commercial product with no open source code to modify, and with no support for third-party software this was eventually deemed to be an inappropriate candidate for the desired LIMS solution. Both Proteios and OpenFreezer are open source projects open for changes and improvements by their users. However, we concluded that we did not wish to utilize an external software package and make ourselves dependent on external developers for future updates. Also, making changes to existing software while at the same time ensuring that the modifications made will integrate seamlessly with updates by the original developers is a tedious process that might take up a significant amount of the bioinformatics resources available, as mentioned in Section~\ref{commercialOrOpenSource}.

For these reasons we chose to develop our own LIMS, enabling us to fully specify and customize the features needed. Thus we would not become dependent on others than ourselves. This choice could also take up a significant amount of bioinformatics resources, but at the other end PROBE ends up with exactly the tool needed.